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1.
Immunology ; 159(2): 167-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31646612

RESUMO

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças do Sistema Endócrino/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/efeitos adversos , Pneumopatias/induzido quimicamente , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/terapia , Doenças do Sistema Endócrino/imunologia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/terapia , Gastroenteropatias/imunologia , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/terapia , Neoplasias/imunologia , Neoplasias/metabolismo , Fatores de Risco , Evasão Tumoral/efeitos dos fármacos
2.
Medicina (B Aires) ; 79(Spec 6/1): 564-569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31864227

RESUMO

In recent times, our understanding of the role of the immune system in different physiopathological situations has increased markedly. A new set of cells, generically known as innate lymphoid cells (ILC), has been discovered in the lymphoid compartment. Five ILC subsets can be recognized according to phenotypic and functional similarities with different subpopulations of T lymphocytes. Unlike T and B lymphocytes, ILC do not express antigen receptors nor undergo selection and clonal expansion upon activation. Instead, they respond rapidly to cytokines and danger signals in infected or inflamed tissues, producing cytokines that direct the immune response toward a type suitable for controlling the initial insult. In addition, ILC establish a crosstalk with other cells of the microenvironment that contributes to the maintenance and restoration of tissue homeostasis. Although many evidences on ILC were obtained from animal models, solid data confirm their existence in humans and their role in various inflammatory disorders. In this article, we address new knowledge on ILC, particularly on their role in the homeostasis of the immune system and in various inflammatory pathologies, in order to present new actors regulating immunity and immunopathology and affecting human health.


Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Enteropatias/imunologia , Pneumopatias/imunologia , Linfócitos/imunologia , Dermatopatias/imunologia , Homeostase/fisiologia , Humanos , Inflamação/fisiopatologia , Enteropatias/fisiopatologia , Pneumopatias/fisiopatologia , Dermatopatias/fisiopatologia
4.
Arthritis Rheumatol ; 71(11): 1943-1954, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31379071

RESUMO

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD). METHODS: Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. RESULTS: Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-γ-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD. CONCLUSION: Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.


Assuntos
Artrite Juvenil/epidemiologia , Proteinose Alveolar Pulmonar/epidemiologia , Distribuição por Idade , Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/imunologia , Artrite Juvenil/patologia , Líquido da Lavagem Broncoalveolar , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-18/imunologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/epidemiologia , Pneumopatias/imunologia , Pneumopatias/patologia , Síndrome de Ativação Macrofágica/epidemiologia , Síndrome de Ativação Macrofágica/imunologia , Masculino , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Transcriptoma , Regulação para Cima
5.
PLoS Pathog ; 15(8): e1007957, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31437249

RESUMO

Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences.


Assuntos
Suplementos Nutricionais , Modelos Animais de Doenças , Pneumopatias/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Virulência/efeitos dos fármacos , Zinco/administração & dosagem , Animais , Feminino , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento
6.
Nat Commun ; 10(1): 3841, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451696

RESUMO

Human lung tissue-resident NK cells (trNK cells) are likely to play an important role in host responses towards viral infections, inflammatory conditions and cancer. However, detailed insights into these cells are still largely lacking. Here we show, using RNA sequencing and flow cytometry-based analyses, that subsets of human lung CD69+CD16- NK cells display hallmarks of tissue-residency, including high expression of CD49a, CD103, and ZNF683, and reduced expression of SELL, S1PR5, and KLF2/3. CD49a+CD16- NK cells are functionally competent, and produce IFN-γ, TNF, MIP-1ß, and GM-CSF. After stimulation with IL-15, they upregulate perforin, granzyme B, and Ki67 to a similar degree as CD49a-CD16- NK cells. Comparing datasets from trNK cells in human lung and bone marrow with tissue-resident memory CD8+ T cells identifies core genes co-regulated either by tissue-residency, cell-type or location. Together, our data indicate that human lung trNK cells have distinct features, likely regulating their function in barrier immunity.


Assuntos
Imunidade nas Mucosas , Células Matadoras Naturais/metabolismo , Pneumopatias/imunologia , Pulmão/citologia , Transcriptoma/imunologia , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Conjuntos de Dados como Assunto , Feminino , Humanos , Células Matadoras Naturais/imunologia , Pulmão/imunologia , Pulmão/cirurgia , Pneumopatias/patologia , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo
7.
Life Sci ; 233: 116671, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336122

RESUMO

Toll-like receptors (TLRs) comprise a clan of proteins involved in identification and triggering a suitable response against pathogenic attacks. As lung is steadily exposed to multiple infectious agents, antigens and host-derived danger signals, the inhabiting stromal and myeloid cells of the lung express an aggregate of TLRs which perceive the endogenously derived damage-associated molecular patterns (DAMPs) along with pathogen associated molecular patterns (PAMPs) and trigger the TLR-associated signalling events involved in host defence. Thus, they form an imperative component of host defence activation in case of microbial infections as well as non-infectious pulmonary disorders such as interstitial lung disease, acute lung injury and airways disease, such as COPD and asthma. They also play an equally important role in lung cancer. Targeting the TLR signalling network would pave ways to the design of more reliable and effective vaccines against infectious agents and control deadly infections, desensitize allergens and reduce inflammation. Moreover, TLR agonists may act as adjuvants by increasing the efficiency of cancer vaccines, thereby contributing their role in treatment of lung cancer too. Overall, TLRs present a compelling and expeditiously bolstered area of research and addressing their signalling events would be of significant use in pulmonary diseases.


Assuntos
Pneumopatias/fisiopatologia , Receptores Toll-Like/metabolismo , Animais , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Transdução de Sinais
8.
Mediators Inflamm ; 2019: 4742634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236064

RESUMO

Chlamydia pneumoniae (Cpn) infection causes multiple acute and chronic human diseases. The role of DCs in host defense against Cpn infection has been well documented. The same is true for invariant natural killer T (iNKT) cells and NK cells, but the interaction among cells is largely unknown. In this study, we investigated the influence and mechanism of iNKT cell on the differentiation and function of NK cell in Cpn lung infection and the role played by DCs in this process. We found that expansion of IFN-γ-producing NK cells quickly happened after the infection, but this response was altered in iNKT knockout (KO) mice. The expression of activation markers and the production of IFN-γ by different NK subsets were significantly lower in KO mice than wild-type (WT) mice. Using in vitro DC-NK coculture and in vivo adoptive transfer approaches, we further examined the role of DCs in iNKT-mediated modulation of NK cell function. We found that NK cells expressed lower levels of activation markers and produced less IFN-γ when they were cocultured with DCs from KO mice than WT mice. More importantly, we found that the adoptive transfer of DCs from the KO mice induced less NK cell activation and IFN-γ production. The results provided evidence on the modulating effect of iNKT cell on NK cell function, particularly the critical role of DCs in this modulation process. The finding suggests the complexity of cellular interactions in Cpn lung infection, which should be considered in designing preventive and therapeutic approaches for diseases and infections.


Assuntos
Infecções por Chlamydophila/imunologia , Chlamydophila pneumoniae/patogenicidade , Células Dendríticas/metabolismo , Células Matadoras Naturais/metabolismo , Pneumopatias/imunologia , Pneumopatias/microbiologia , Animais , Feminino , Interferon gama/metabolismo , Pneumopatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Semin Ultrasound CT MR ; 40(3): 213-228, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31200870

RESUMO

Immune-mediated lung diseases are a complex group of diseases characterized by inflammatory cellular infiltration of the lungs which can result in progressive airway remodeling and parenchymal injury. Diseases have variable presentation depending on antigen exposure, patient predisposition, and type of immune response. Early recognition, removal of the inciting antigen, and steroid intervention are important to prevent disease progression. This article will review key clinical, radiologic, and pathologic features of immune-mediated lung diseases.


Assuntos
Diagnóstico por Imagem/métodos , Pneumopatias/imunologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/patologia
10.
Adv Protein Chem Struct Biol ; 116: 311-345, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31036295

RESUMO

Aquaporins (AQPs) are a family of membrane water channel proteins that osmotically modulate water fluid homeostasis in several tissues; some of them also transport small solutes such as glycerol. At the cellular level, the AQPs regulate not only cell migration and transepithelial fluid transport across membranes, but also common events that are crucial for the inflammatory response. Emerging data reveal a new function of AQPs in the inflammatory process, as demonstrated by their dysregulation in a wide range of inflammatory diseases including edematous states, cancer, obesity, wound healing and several autoimmune diseases. This chapter summarizes the discoveries made so far about the structure and functions of the AQPs and provides updated information on the underlying mechanisms of AQPs in several human inflammatory diseases. The discovery of new functions for AQPs opens new vistas offering promise for the discovery of mechanisms and therapeutic opportunities in inflammatory disorders.


Assuntos
Aquaporinas/metabolismo , Inflamação/metabolismo , Água/metabolismo , Animais , Aquaporinas/análise , Aquaporinas/imunologia , Autoimunidade , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/metabolismo , Humanos , Inflamação/imunologia , Nefropatias/imunologia , Nefropatias/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Modelos Moleculares
11.
AJR Am J Roentgenol ; 213(3): 549-554, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31039026

RESUMO

OBJECTIVE. The purpose of this study is to assess the most common causes of the reverse halo sign (RHS) in immunocompromised patients and to identify clinicoradiologic features that help in achieving a specific diagnosis. MATERIALS AND METHODS. This retrospective study included 70 patients with hematologic malignancy, neutropenia, or history of solid organ transplant or stem cell transplant who had the RHS at chest CT. Absolute neutrophil count, imaging features of the RHS, and presence of pleural effusions were noted and correlated with the specific diagnosis. A decision tree was constructed from predictive imaging features and compared with radiologist assessment for infectious versus noninfectious cause. RESULTS. Infection, including fungal and bacterial pneumonia, was the most common cause of the RHS (66%), followed by organizing pneumonia (26%). Noninfectious causes such as organizing pneumonia were more likely in the solid organ transplant group, whereas infections were more likely in patients with hematologic malignancy and stem cell transplant. Among fungal pneumonias, aspergillosis (20%) was as common as mucormycosis (19%). In univariate analysis, neutropenia, rim thickness, central ground-glass attenuation, and lesion diameter correlated with infectious cause. A decision tree using neutropenia, rim thickness, central ground-glass attenuation, and pleural effusion could differentiate infectious from noninfectious cause with accuracy of 78%, compared with radiologist accuracy of 81%. CONCLUSION. Infections are more likely to cause RHS than noninfectious processes in immunocompromised patients, and aspergillosis may be as likely overall as mucormycosis because of its higher frequency in these patients. A decision tree using clinical and imaging features can help differentiate infectious from noninfectious causes of RHS.


Assuntos
Hospedeiro Imunocomprometido , Pneumopatias/diagnóstico por imagem , Pneumopatias/imunologia , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Árvores de Decisões , Diagnóstico Diferencial , Feminino , Humanos , Pneumopatias Fúngicas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico por imagem , Pneumonia/diagnóstico por imagem , Estudos Retrospectivos
12.
Iran J Allergy Asthma Immunol ; 18(2): 218-224, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066258

RESUMO

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1ß, IL-18, and IL-1ßR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Substâncias para a Guerra Química/efeitos adversos , Inflamassomos/metabolismo , Interleucina-1/metabolismo , Pneumopatias/imunologia , Gás de Mostarda/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-1/sangue , Interleucina-1/genética , Interleucina-18/sangue , Guerra do Iraque 2003-2011 , Pneumopatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , Veteranos
14.
Food Funct ; 10(4): 2209-2220, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30945705

RESUMO

Ginkgo biloba has long been used in ancient China for the treatment of cough, asthma, and other lung diseases. However, the active constituents in G. biloba for pulmonary disease treatment remain unclear. The objective of this study was to evaluate the anti-inflammatory active constituents in G. biloba and clarify their associated molecular mechanisms. The biological effects of different G. biloba extracts were evaluated in an ovalbumin-induced allergic mouse model. Anti-inflammatory compounds were present in the ethyl acetate phase of the extract, which were analysed by HPLC-MS. Biflavones were identified as the main compounds, which were further evaluated by docking calculations. Leukocyte elastase showed a high fit score with ginkgetin, one of the identified biflavones. The lowest binding free energy was -6.69 kcal mol-1. The effects of biflavones were investigated in vivo and in vitro. Ginkgetin markedly suppressed the abnormal expression of the Akt and p38 pathways in human neutrophil elastase (HNE)-stimulated A549 cells. Biflavones also decreased MUC5AC mRNA expression in HNE-stimulated A549 cells and the allergic mouse model. Inflammatory cells (neutrophils) and cytokines (IL-8) also decreased in mice treated with biflavones. The results suggest that G. biloba biflavones could inhibit the activity of leukocyte elastase. This in turn implicates G. biloba as a functional food for the treatment of airway inflammation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Ginkgo biloba/química , Pneumopatias/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Animais , Anti-Inflamatórios/isolamento & purificação , Biflavonoides/administração & dosagem , Biflavonoides/química , Biflavonoides/isolamento & purificação , Feminino , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Pneumopatias/genética , Pneumopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucina-5AC/genética , Mucina-5AC/imunologia , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química
15.
J Immunol ; 202(9): 2519-2526, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31010841

RESUMO

Inducible bronchus-associated lymphoid tissue (iBALT) is a tertiary lymphoid structure that resembles secondary lymphoid organs. iBALT is induced in the lung in response to Ag exposure. In some cases, such as infection with Mycobacterium tuberculosis, the formation of iBALT structure is indicative of an effective protective immune response. However, with persistent exposure to Ags during chronic inflammation, allergy, or autoimmune diseases, iBALT may be associated with exacerbation of inflammation. iBALT is characterized by well-organized T and B areas enmeshed with conventional dendritic cells, follicular dendritic cells, and stromal cells, usually located surrounding airways or blood vessels. Several of the molecular signals and cellular contributors that mediate formation of iBALT structures have been recently identified. This review will outline the recent findings associated with the formation and maintenance of iBALT and their contributions toward a protective or pathogenic function in pulmonary disease outcome.


Assuntos
Brônquios/imunologia , Células Dendríticas Foliculares/imunologia , Células Dendríticas/imunologia , Imunidade nas Mucosas , Pneumopatias/imunologia , Tecido Linfoide/imunologia , Animais , Brônquios/patologia , Células Dendríticas/patologia , Células Dendríticas Foliculares/patologia , Humanos , Pneumopatias/patologia , Tecido Linfoide/patologia
16.
Int J Mol Sci ; 20(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965568

RESUMO

Emerging evidence suggests that platelets, cytoplasmic fragments derived from megakaryocytes, can no longer be considered just as mediators in hemostasis and coagulation processes, but as key modulators of immunity. Platelets have received increasing attention as the emergence of new methodologies has allowed the characterization of their components and functions in the immune continuum. Platelet activation in infectious and allergic lung diseases has been well documented and associated with bacterial infections reproduced in several animal models of pulmonary bacterial infections. Direct interactions between platelets and bacteria have been associated with increased pulmonary platelet accumulation, whereas bacterial-derived toxins have also been reported to modulate platelet function. Recently, platelets have been found extravascular in the lungs of patients with asthma, and in animal models of allergic lung inflammation. Their ability to interact with immune and endothelial cells and secrete immune mediators makes them one attractive target for biomarker identification that will help characterize their contribution to lung diseases. Here, we present an original review of the last advances in the platelet field with a focus on the contribution of platelets to respiratory infections and allergic-mediated diseases.


Assuntos
Plaquetas/fisiologia , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Animais , Plaquetas/metabolismo , Humanos
17.
Vet Pathol ; 56(5): 703-710, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30866742

RESUMO

Equine herpesvirus 1 (EHV-1) uses equine major histocompatibility complex class I (MHC class I) as an entry receptor. Exogenous expression of equine MHC class I genes in murine cell lines confers susceptibility to EHV-1 infection. To examine the in vivo role of equine MHC class I as an entry receptor for EHV-1, we generated transgenic (Tg) mice expressing equine MHC class I under the control of the CAG promoter. Equine MHC class I protein was expressed in the liver, spleen, lung, and brain of Tg mice, which was confirmed by Western blot. However, equine MHC class I antigen was only detected in bronchiolar epithelium and not in other tissues, using the immunofluorescence method employed in this study. Both Tg and wild-type (WT) mice developed pneumonia 3 days after intranasal infection with EHV-1. The bronchiolar epithelial cells of Tg mice showed more severe necrosis, compared with those in WT mice. In addition, the number of virus antigen-positive cells in the lungs was higher in Tg mice than in WT mice. These results suggest that exogenous expression of equine MHC class I renders mice more susceptible to EHV-1 infection.


Assuntos
Infecções por Herpesviridae/imunologia , Herpesvirus Equídeo 1 , Antígenos de Histocompatibilidade Classe I/metabolismo , Cavalos , Pneumopatias/virologia , Animais , Antígenos de Histocompatibilidade Classe I/genética , Pneumopatias/imunologia , Camundongos , Camundongos Transgênicos
18.
J Immunol ; 202(8): 2482-2492, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30867239

RESUMO

The TNFR superfamily member 4-1BB is important in the establishment of tissue-resident memory T cells (Trm) in the lung tissue following influenza infection. Moreover, supraphysiological boosting of 4-1BB in the airways during the boost phase of a prime-boost immunization regimen increases the long-lived Trm population, correlating with increased protection against heterotypic challenge. However, little is known about how 4-1BB contributes to the establishment of the lung Trm population. In this study, we show that effects of 4-1BB on lung Trm accumulation are already apparent at the effector stage, suggesting that the major role of 4-1BB in Trm formation is to allow persistence of CD8 T effector cells in the lung as they transition to Trm. Using supraphysiological stimulation of 4-1BB in the boost phase of a prime-boost immunization, we show that the effect of 4-1BB on Trm generation requires local delivery of both Ag and costimulation, is inhibited by rapamycin treatment during secondary CD8 effector T cell expansion, and is dependent on the signaling adaptor TRAF1. The decrease in lung Trm following early rapamycin treatment is accompanied by increased circulating memory T cells, as well as fewer effectors, suggesting a role for mammalian target of rapamycin (mTOR) in the formation of Trm through effects on the accumulation of effector precursors. Taken together, these data point to an important role for 4-1BB, TRAF1, and mTOR in the persistence of CD8 effector T cells in the lung parenchyma, thereby allowing the transition to Trm.


Assuntos
Ligante 4-1BB/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A/imunologia , Pneumopatias/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Fator 1 Associado a Receptor de TNF/imunologia , Serina-Treonina Quinases TOR/imunologia , Ligante 4-1BB/genética , Animais , Linfócitos T CD8-Positivos/patologia , Pulmão/patologia , Pulmão/virologia , Pneumopatias/genética , Pneumopatias/patologia , Pneumopatias/virologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , Fator 1 Associado a Receptor de TNF/genética , Serina-Treonina Quinases TOR/genética
19.
BMC Infect Dis ; 19(1): 263, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885152

RESUMO

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) can deteriorate rapidly to become fatal. Reported poor prognostic factors include radiographic findings, undernutrition, anemia and high inflammation test values. However, the association of these prognostic factors with the pathophysiology of the disease remains unknown. We aimed to clarify the pathophysiology of MAC-LD and develop a new biomarker that reflects the immune response to the disease. METHODS: We performed the cytokine panel analyses of serum from patients with MAC-LD and compared each cytokine level with clinically negative prognostic factors (radiographic disease type, body mass index, albumin, C-reactive protein and hemoglobin) and high-resolution CT scores. RESULTS: We analyzed 27 patients with MAC-LD, 6 with the fibrocavitary form and 21 with the nodular bronchiectatic form on high-resolution CT. Serum CXC motif ligand 10 (CXCL10) concentration was significantly elevated in patients with the fibrocavitary form (p = 0.008). CXCL10 levels correlated with body mass index (r = - 0.60, p = 0.0008), serum albumin concentration (r = - 0.45, p = 0.016) and high-resolution CT scores (r = 0.61, p = 0.0006). Among 14 patients initially untreated, antibiotic therapy was initiated for five during the study period. CXCL10 concentration was significantly higher in these patients (p = 0.046), and receiver operating characteristic analysis for CXCL10 concentration on treatment initiation produced an area under the curve of 0.844, with a sensitivity of 100%, specificity of 66.7%, and cut-off value of 366.5 pg/mL. CONCLUSION: We revealed cytokine profiles in patients with MAC-LD. Serum CXCL10 levels probably reflect the severity of MAC-LD. Our findings suggest that CXCL10 concentration may be a promising biomarker for managing treatment for patients with MAC disease of the lung.


Assuntos
Quimiocina CXCL10/sangue , Citocinas/sangue , Pneumopatias/imunologia , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/imunologia , Idoso , Antibacterianos , Biomarcadores , Índice de Massa Corporal , Bronquiectasia/imunologia , Bronquiectasia/microbiologia , Feminino , Humanos , Pulmão , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Sensibilidade e Especificidade
20.
Artigo em Inglês | MEDLINE | ID: mdl-30880949

RESUMO

Background: While chronic respiratory diseases are among the leading causes of mortality and morbidity worldwide, little is known about the effect of blood eosinophil levels on lung function trajectories among healthy individuals. Methods: We analyzed data of apparently healthy individuals (n=18,089) recruited for the Tel Aviv Medical Center Inflammation Survey. Blood eosinophil levels were compared between participants with normal and those with abnormal lung function. Multivariate regression was used to assess the OR of forced expiratory volume in 1 second (FEV1) deterioration according to baseline eosinophils in subjects with normal lung function (n=4,141) during a follow-up period of 4 years. Results: Participants with an abnormal, as opposed to a normal, pulmonary function test (PFT) (n=1,832, 10.1%) had significantly higher eosinophil levels, expressed as a percentage or count (2.99%±2.00% compared to 2.67%±1.88% and 0.2210e3/µL±0.163/µL compared to 0.1810e3/µL±0.183/µL, respectively; P<0.001 for both). Among participants with a normal PFT at baseline, those with an eosinophil percentage higher than 4% showed a higher risk for FEV1 decline above 60 mL/year (OR=1.199, 95% CI=1.005-1.431, P=0.044). Conclusion: Our study suggests that higher blood eosinophil levels can predict PFT deterioration even in apparently healthy subjects, implying that these individuals could benefit from frequent lung function evaluation.


Assuntos
Eosinófilos/imunologia , Pneumopatias/diagnóstico , Pulmão/fisiopatologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Israel , Contagem de Leucócitos , Pneumopatias/sangue , Pneumopatias/imunologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Espirometria , Fatores de Tempo , Capacidade Vital
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